The neurological manifestations of HIV-1 affect approximately one-quarter of adults with AIDS. In addition to super-infections with opportunistic organisms and malignancy, damage in the CNS in AIDS appears to be most closely associated with toxins released by brain microglia/macrophages that have been infected by HIV or stimulated by the viral coat protein, gp!20. Neurons themselves are most likely not infected, but undergo dendritic and synaptic injury and may succumb to apoptosis. At least part of this damage is accounted for by macrophage and possibly astrocyte toxic factors leading to overexcitation of glutamate receptors, especially of the W-methyl-D-aspartate subtype (NMDARs), as shown previously by this grant. Also, this grant helped develop the first clinically-tolerated NMDAR antagonist, Memantine, which led to phase 2 clinical trials for HIV-associated dementia. Here we propose to develop a class of NMDAR antagonists that are superior to Memantine. These new drugs are termed NO-Memantines and are being developed to prevent neuronal injury engendered by gp!20 in the following model systems: (a) in vitro in rodent cerebrocortical cultures, (b) in vivo in a rodent retinal model using intravitreal injection of gp!20 into the eye, and (c) in vivo in a gp120- transgenic mouse model. Additionally, our group has cloned and characterized a new family of NMDAR subunits, called NR3, which when combined with conventional NR1 and NR2 subunits, lead to decreased NMDAR activity, in a sense mimicking the effect of Memantine. Here we propose to study the effect of NR3 on gp!20-induced neuronal damage in similar models to those used for drug testing. We have produced NR3 knockout and transgenic mice to breed with gp!20-transgenic mice for this purpose. The resulting mice will be analyzed histologically by confocal/deconvolution microscopy and behaviorally for evidence of amelioration of gp!20-induced damage. This molecular approach using NR3 subunits will be used to validate the effect of drugs that inhibit excessive NMDAR activity to protect neurons from gp120-induced damage. It is anticipated that these preclinical studies investigating the role of the NMDAR in neuronal cell injury may lead to new treatments for the neurological manifestations of AIDS.